Key result
Coexpression of alpha 2/delta and beta 2A subunits synergistically increased whole-cell Ca2+ channel current >100-fold, driven by changes in channel gating and alpha 1 protein levels.
The synergistic enhancement of macroscopic Ca2+ currents by alpha 2/delta and beta 2A subunits is primarily due to synergistic changes in channel gating, while alpha 2/delta also increases alpha 1 protein expression in the plasma membrane.
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Caution against clinical extrapolation; extends in vitro evidence for subunit synergy and leaves open native cardiomyocyte validation.
A combined biochemical and electrophysiological approach was used to determine the mechanism by which the auxiliary subunits of Ca2+ channel enhance the macroscopic Ca2+ currents. Xenopus oocytes were injected with RNA of the main pore-forming subunit (cardiac: alpha 1C), and various combinations of RNAs of the auxiliary subunits (alpha 2/delta and beta 2A). 2. The single channel open probability (Po; measured at 0 mV) was increased approximately 3-, approximately 8- and approximately 35-fold by alpha 2/delta, beta 2A and alpha 2/delta+beta 2A, respectively. The whole-cell Ca2+ channel current was increased approximately 8- to 10-fold by either alpha 2/delta or beta 2A, and synergistically > 100-fold by alpha 2/delta+beta 2A. The amount of 35S-labelled alpha 1 protein in the plasma membrane was not changed by coexpression of beta 2A, but was tripled by coexpression of alpha 2/delta (either with or without beta). 3. We conclude that the increase in macroscopic current by alpha 2/delta is equally due to changes in amount of alpha 1 in the plasma membrane and an increase in Po, whereas all of the effect of beta 2A is due to an increase in Po. The synergy between alpha 2/delta and beta in increasing the macroscopic current is due mainly to synergistic changes in channel gating.
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Shistik et al. (1995) studied this question. Coexpression of auxiliary subunits (alpha 2/delta and beta 2A) vs. alpha 1C subunit alone was evaluated on Single channel open probability and whole-cell Ca2+ channel current. Coexpression of alpha 2/delta and beta 2A subunits synergistically increased whole-cell Ca2+ channel current >100-fold, driven by changes in channel gating and alpha 1 protein levels.
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